Increased blood flow by glucose infusion, diabetes, and hypoxia is linked to reductive stress manifested by an increased lactate/pyruvate (L/P) ratio (indicative of an increased cytosolic ratio of free NADH/NAD+). This (and other) evidence predicts that blood flow may be modulated by L/P independent of hyperglycemia, hypoxia, and lactate levels. To test this prediction, normal male Sprague-Dawley rats were anesthetized with 45 mg/kg pentobarbital, an indwelling catheter was placed in the femoral vein, and rats were allowed free movement after recovery. 18 hours later, rats were infused for 5 h at a rate of 9 m./kg body wt/h with saline (S) or 150 mM Na L-lactate (22.5 umole/kg/min) (L) + 3 mM Na pyruvate (0.45 umole.kg/min) (L+P_ (n=5 for each group). Rats were than anesthetized with 100 mg/kg thiopental and blood flow (ml/min/g wet wt) was assessed with 10 um 46Sc microspheres. Final plasma lactate levels were 1.25+0.46(SD) mM in S, 2.61+0.82 in L (p=0.002 vs S), and 2.12+0.43 in L+P(p=0.020 vs S and p=0.234 vs L+P). Plasma pH was 7.45+0.05 in S. 7.54+0.03 in L p=0.012 vs S), and 7.56+0.03 in L+P (p=0.002 vs S and p=0.358 vs L). Lactate infusion had no effect on plasma glucose levels or mean arterial blood presser. Retinal blood flows were 0.38+0.02 in S, 0.55+0.02 in L (p=0.003 vs S), and 0.38+0.01 in L+P p=0.86 vs S and p=0.002 vs L). Sciatic nerve blood flows were 0.065+0.10 in S, 0.157+0.022 in L (p=0.003 vs S, and 0.061+0.003 in L+P (p=0.6623 vs S and p=0.001 vs L). Lactate infusion also increased blood flow in skeletal muscle, skin, and diaphragm, but not in brain or heart. These observations indicate that: 1) lactate infusion, like glucose infusion, increases retinal and sciatic nerve blood flow, and 2) coinfusion of pyruvate prevents blood flow increases induced by lactate and by glucose. These findings suggest that increased retinal and sciatic nerve blood flow induced by diabetes is mediated by reductive stress which precedes and contributes to hypoxic retinopathy and neuropathy.